Identifying APOE related lipid biomarkers for diagnosing chronic neurocognitive deficits in TBI patients

创伤性脑损伤（TBI）影响了来自伊拉克自由行动（OIF）/行动的30多万士兵 持久自由（OEF）。轻度TBI（mTBI）是这些冲突中最常见的脑损伤， 占所有脑损伤的90%然而，mTBI的临床表现与受试者重叠 患有创伤后应激障碍（PTSD），这也是一种普遍的情况， 从OIF/OEF返回的士兵。TBI的病理生理学仍然难以解剖，因为 在军事人口中发生的伤害的异质性。大量的神经病理学研究 使用职业橄榄球运动员和退伍军人的脑组织，他们在生活中遭受了TBI， 淀粉样蛋白和tau蛋白的积累，这两者都是阿尔茨海默病（AD）的关键病理。最近 研究表明，在患有mTBI的受试者的血液中，血液Aβ和tau水平也改变。进行的研究 Roskamp研究所的科学家和其他人的研究表明，携带载脂蛋白（APOE）ε4等位基因的个体 并且TBI的诊断患有与AD一致的学习和记忆障碍。 然而，在mTBI受试者中检测AD相关病理仍然是一个关键的挑战，因此， 血液生物标志物的发现将极大地增强我们在患有mTBI的受试者中检测临床前AD的能力。 我们已经证明，血液中的omega-3和omega-6多不饱和脂肪酸（PUFA）含量 磷脂（PL）在患有临床前轻度认知障碍（MCI）或AD的ε4携带者中改变。这些 与对照组和非ε4携带者相比，患有TBI的ε4携带者的血液PL也发生了改变。ω-3和 ω-6 PUFA可以经历一系列酶促和非酶促过程， 生物活性脂质代谢物，其影响一系列炎症和氧化应激参数， 与AD和TBI病理学相关。鞘磷脂（SM）水平在AD和TBI患者中改变， 这些脂质可以进一步代谢产生神经酰胺，其是炎症的有效调节剂。我们 因此假设对生物活性脂质代谢物（即类二十烷酸，异前列烷， 消退素、脂氧素、神经酰胺和鞘氨醇）将可用于区分mTBI受试者与健康受试者。 对照组和具有类似症状的病症的患者。这些生物活性脂质代谢物将 也有助于预测认知能力下降，这表明随后的AD风险。我们已经开发了脂质组学分析， 利用纳米级超高压液相色谱（UHPLC）系统和 Q-Exactive混合四极轨道阱质量的质量精度和高分辨率能力 光谱仪，使我们能够有效，准确地识别和定量数百种生物活性脂质 代谢物。我们将应用这项技术来鉴定新的血脂代谢物， 来自其他诊断组的mTBI受试者。我们将确定人内和人与人之间的变化， 血脂代谢物，以确定那些具有低变异性的代谢物，然后对其进行纵向评价， 短期和长期。从这些研究中，我们将确定与认知功能相关的代谢物， mTBI受试者经历的下降。本文提出的工作将在很大程度上使用现有的样本 生物储存库中的可用数据，这些数据是从入组慢性效应研究的受试者中收集的。 神经创伤协会和军队。我们希望，所提出的脂质组学技术， 与载脂蛋白E基因型信息，将使我们能够开发一个生物标志物面板，将有助于临床医生， 提供mTBI的准确诊断和AD相关认知障碍的预后， mTBI。这些研究将提高我们的能力，为患有糖尿病的患者提供更好的护理和疾病管理。 mTBI，以降低他们发展AD和相关疾病的风险。

Traumatic brain injury (TBI) affects over 300,000 troops from the Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF). Mild TBI (mTBI) is the most prevalent brain injury from these conflicts and represents 90% of all brain injuries. However, clinical presentation of mTBI overlaps with those of subjects suffering from post-traumatic stress disorder (PTSD), which is also a prevalent condition that afflicts 30% of the soldiers returning from the OIF/OEF. The pathophysiology of TBI remains difficult to dissect owing to the heterogenous nature of the injuries that occur in the military population. A number of neuropathological studies using brain tissue from professional football players and military veterans who sustained TBI in life showed accumulation of amyloid and tau, both of which are key pathologies of Alzheimer's disease (AD). Recent studies show that blood Aβ and tau levels are also altered in blood of subjects with mTBI. Studies conducted by the Roskamp Institute scientists and others showed that individuals with the apolipoprotein (APOE) ε4 allele and a diagnosis of TBI suffered from learning and memory impairment that was consistent with AD. Nevertheless, detecting AD related pathology in mTBI subjects remains a critical challenge and therefore discovery of blood biomarkers will greatly enhance our ability to detect preclinical AD in subjects with mTBI. We have shown that omega-3 and omega-6 polyunsaturated fatty acid (PUFA) content within blood phospholipids (PL) are altered in ε4 carriers with preclinical mild cognitive impairment (MCI) or AD. These blood PL are also altered in ε4 carriers with TBI compared to controls and non-ε4 carriers. The omega-3 and omega-6 PUFA can undergo a series of enzymatic and non-enzymatic processes which result in generation of bioactive lipid metabolites that influence a range of inflammatory and oxidative stress parameters which are relevant to both AD and TBI pathologies. Levels of sphingomyelin (SM) are altered in AD and TBI patients and these lipids can be further metabolized to generate ceramides that are potent modulators of inflammation. We therefore hypothesize that an examination of bioactive lipid metabolites (i.e. eicosanoids, isoprostanes, resolvins, lipoxins, ceramides and sphingosine) will be useful in differentiating mTBI subjects from healthy controls and those with conditions which present with similar symptoms. These bioactive lipid metabolites will also help predict cognitive decline indicative of subsequent AD risk. We have developed lipidomic assays that take advantage of the nano-flow Ultra high pressure liquid chromatography (UHPLC) systems and the high mass accuracy and high resolution capabilities of the Q-Exactive hybrid quadruple Orbitrap mass spectrometer, allowing us to efficiently and accurately identify and quantify hundreds of bioactive lipid metabolites. We will apply this technology to identify novel blood lipid metabolites that can differentiate subjects with mTBI from other diagnostic groups. We will determine the intra- and inter-person variations of blood lipid metabolites to identify those with low variability which will then be evaluated longitudinally over short- and long-term periods. From these studies, we will identify metabolites that are associated with cognitive decline experienced by subjects with mTBI. The work proposed herein will largely use the existing samples available in the bio-repositories that were collected from subjects enrolled in the Chronic Effects of Neurotrauma Consortium and military cohorts. We expect that the proposed lipidomics technology, together with the APOE genotype information, will allow us to develop a biomarker panel that will aid clinicians in providing an accurate diagnosis of mTBI and in prognosis of cognitive impairment associated with AD after mTBI. These studies will improve our ability to provide better care and disease management to patients with mTBI in order to reduce their risk of developing AD and related disorders.